NM_000098.3(CPT2):c.338C>T (p.Ser113Leu) AND Carnitine palmitoyl transferase II deficiency, severe infantile form

Germline classification:: Pathogenic/Likely pathogenic (8 submissions)
Last evaluated:: Feb 1, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000576571.26

Allele description [Variation Report for NM_000098.3(CPT2):c.338C>T (p.Ser113Leu)]

NM_000098.3(CPT2):c.338C>T (p.Ser113Leu)

Gene:

CPT2:carnitine palmitoyltransferase 2 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

1p32.3

Genomic location:

Preferred name:

NM_000098.3(CPT2):c.338C>T (p.Ser113Leu)

Other names:

p.S113L:TCG>TTG

HGVS:

NC_000001.11:g.53202427C>T
NG_008035.1:g.10999C>T
NM_000098.3:c.338C>TMANE SELECT
NM_001330589.2:c.338C>T
NP_000089.1:p.Ser113Leu
NP_000089.1:p.Ser113Leu
NP_001317518.1:p.Ser113Leu
NC_000001.10:g.53668099C>T
NM_000098.2:c.338C>T
P23786:p.Ser113Leu
c.338C>T (p.Ser113Leu)

Protein change:

S113L; SER113LEU

Links:

UniProtKB: P23786#VAR_001392; OMIM: 600650.0002; dbSNP: rs74315294

NCBI 1000 Genomes Browser:

rs74315294

Molecular consequence:

NM_000098.3:c.338C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001330589.2:c.338C>T - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Carnitine palmitoyl transferase II deficiency, severe infantile form
Synonyms:: CARNITINE PALMITOYLTRANSFERASE II DEFICIENCY WITH HYPOKETOTIC HYPOGLYCEMIA; CARNITINE PALMITOYLTRANSFERASE II DEFICIENCY, HEPATOCARDIOMUSCULAR; CPT II DEFICIENCY, HEPATIC; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0010914; MedGen: C1833511; Orphanet: 228305; OMIM: 600649

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000807602	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Sep 1, 2017)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 8358442, 9600456, 23184072, 22975760, 10090476, 25741868, 25326635
SCV001150076	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	criteria provided, single submitter (Classification criteria August 2017)	Pathogenic (Mar 17, 2020)	germline	clinical testing	Citation Link,
SCV001194229	Myriad Genetics, Inc.	criteria provided, single submitter (Myriad Women's Health Autosomal Recessive and X-Linked Classification Criteria (2019))	Pathogenic (Oct 18, 2019)	unknown	clinical testing	PubMed (4) [See all records that cite these PMIDs] 21913903, 16996287, 15642848, 835844 Citation Link,
SCV001652884	Pars Genome Lab	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (May 18, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001810369	Genome-Nilou Lab	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jul 22, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV003841325	3billion	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 23, 2023)	unknown	clinical testing	PubMed (7) [See all records that cite these PMIDs] 8358442, 11994355, 20810031, 27123472, 26477380, 14615409, 25741868
SCV003935106	Eurofins-Biomnis	criteria provided, single submitter (Accession Criteria ClinVar Biomnis)	Likely pathogenic (Dec 2, 2022)	biparental	clinical testing	Citation Link,
SCV005051731	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 1, 2024)	germline	curation	PubMed (1) [See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	biparental	yes	1	not provided	not provided	1	not provided	clinical testing
not provided	germline	yes	2	not provided	not provided	2	not provided	clinical testing
not provided	unknown	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	no	not provided	not provided	not provided	not provided	not provided	clinical testing, curation

Citations

PubMed

Two CPT2 mutations in three Japanese patients with carnitine palmitoyltransferase II deficiency: functional analysis and association with polymorphic haplotypes and two clinical phenotypes.

Wataya K, Akanuma J, Cavadini P, Aoki Y, Kure S, Invernizzi F, Yoshida I, Kira J, Taroni F, Matsubara Y, Narisawa K.

Hum Mutat. 1998;11(5):377-86.

PubMed [citation]

PMID:: 9600456

Clinically symptomatic heterozygous carnitine palmitoyltransferase II (CPT II) deficiency.

Joshi PR, Deschauer M, Zierz S.

Wien Klin Wochenschr. 2012 Dec;124(23-24):851-4. doi: 10.1007/s00508-012-0296-9. Epub 2012 Nov 27.

PubMed [citation]

PMID:: 23184072

See all PubMed Citations (16)

Details of each submission

From Baylor Genetics, SCV000807602.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing (GTR000508680.4)	PubMed (7)

Description

This mutation has been previously reported as disease-causing and was found once in our laboratory in trans with a frameshift mutation in a 1-year-old female with IUGR, global delays, spastic tetraparesis, brain calcifications and leukomalacia, and a similarly affected brother (who was a single heterozygote; did not carry the frameshift mutation). Heterozygotes are expected to be asymptomatic carriers.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided	(GTR000508680.4)	not provided	not provided	not provided	not provided

From Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München, SCV001150076.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	not provided
2	not provided	1	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	1	blood	not provided		1	not provided	not provided	not provided
2	germline	yes	1	blood	not provided		1	not provided	not provided	not provided

From Myriad Genetics, Inc., SCV001194229.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

NM_000098.2(CPT2):c.338C>T(S113L) is classified as pathogenic in the context of carnitine palmitoyltransferase II deficiency. Please note that the S113L variant is associated with the myopathic form of carnitine palmitoyltransferase II deficiency. Disease phenotype is dependent on, but not necessarily predicted by, the combination of variants inherited. Sources cited for classification include the following: PMID 21913903, 16996287, 15642848 and 835844. Classification of NM_000098.2(CPT2):c.338C>T(S113L) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Pars Genome Lab, SCV001652884.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	no	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Genome-Nilou Lab, SCV001810369.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	no	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From 3billion, SCV003841325.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

Description

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.139%). Protein truncation variants are a common disease-causing mechanism. Functional studies provide supporting evidence of the variant having a damaging effect on the gene or gene product (PMID: 26477380, 27123472, 8358442). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.89; 3Cnet: 0.34). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000008953 / PMID: 8358442). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least 2 similarly affected unrelated individuals (PMID: 11994355, 14615409, 20810031). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Eurofins-Biomnis, SCV003935106.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	biparental	yes	1	not provided	not provided		1	not provided	not provided	not provided

From Laboratory of Medical Genetics, National & Kapodistrian University of Athens, SCV005051731.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	no	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Nov 30, 2024

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